Unveiling an Immunological Mystery: Deciphering the Durability Divide Between Infection and Vaccine-Elicited Antibody Responses

Abstract

Achieving durable antibody-mediated protection remains critical in vaccine develop-ment, particularly for viral diseases like COVID-19 and HIV. We discuss factors influencing an-tibody durability, highlighting the role of long-lived plasma cells (LLPCs) in the bone marrow, which are essential for sustained antibody production over many years. The frequencies and prop-erties of bone marrow LLPC are critical determinants of the broad spectrum of antibody durability for different vaccines. Vaccines for diseases like measles and mumps elicit long-lasting antibod-ies; those for COVID-19 and HIV do not. High epitope densities in the vaccine are known to favor antibody durability, but we discuss three underappreciated variables that also play a role in long-lived antibody responses. First, in addition to high epitope densities, we discuss the im-portance of CD21 as a critical determinant of antibody durability. CD21 is a B cell antigen recep-tor (BCR) complex component. It significantly affects BCR signaling strength in a way essential for generating LLPC in the bone marrow. Second, all antibody-secreting cells (ASC) are not cre-ated equal. There is a four-log range of antibody secretion rates, and we propose epigenetic im-printing of different rates on ASC, including LLPC, as a factor in antibody durability. Third, antibody durability afforded by bone marrow LLPC is independent of continuous antigenic stim-ulation. By contrast, tissue-resident T-bet+CD21low ASC also persists in secondary lymphoid tissues and continuously produces antibodies depending on persisting antigen and the tissue mi-croenvironment. We discuss these variables in the context of making an HIV vaccine that elicits broadly neutralizing antibodies against HIV that persist at protective levels without continuous vaccination over many years.